33 The concept of a gene revisited There are multiple haplotypes that account for a significant, fraction of human genomic variability. The initial results clearly challenge the concept of the gene, and particularly the view that there exists one predominant form of a gene as the wild-type and various rare or mutant forms. This may well indicate the beginning of the end

of Mendel’s world10 and its view of the amount, nature, pattern, and structure of genetic variation. Inhibitors,research,lifescience,medical The two-allele concept, of the gene may for the time being have been nothing but the extreme and visible end of an entire spectrum, given the (until recently) limited access to genetic variation. Studies to come that will analyze continuously increasing numbers of individuals and increasingly larger, eventually complete gene regions (which may well extend up to about 100 Inhibitors,research,lifescience,medical kb and more) are likely to generate even more complex results. In brief, the concept of a gene may have to be revised completely10,29,33: the gene as a concrete molecular substrate does not exist. Genes rather appear to exist, as a spectrum of different, forms; the gene will have to be redefined as the sum of its haplotypes. The definition of a gene will have to include the positions, population specificities, and characterization of its variants, and a precise

Inhibitors,research,lifescience,medical description of its haplotype structures. It is obvious that the next level of description (and the first step to reduce haplotype complexity) will be the assignment of the sequence haplotypes to the protein isoforms they

Inhibitors,research,lifescience,medical constitute. Needless to say that such a revision of the concept. of the gene will have profound consequences on the analysis and classification of gene function, as well as its role as a drug target. Genetic variability and its implications for pharmacogenomics and a personalized medicine Knowledge on genetic variation and haplotype structures: an essential prerequisite for drug target discovery and optimization The approaches and research data outlined above raise two major issues. First, Inhibitors,research,lifescience,medical how do the different approaches to candidate gene analysis apply to the various aspects of pharmacogenomics? Second, which conclusions and consequences should be drawn, taking into account, the recent results demonstrating potentially abundant candidate gene sequence diversity and complex haplotype structures? With respect Olopatadine to the first, issue, all the entire individually variable candidate gene sequences corresponding to the gene-based functional haplotypes described earlier are the immediate NLG-8189 order correlates of pharmaceutical relevance as (i) the potential molecular correlates of the disease genes and naturally occurring different, forms of the genes, since they provide the immediate links to gene function(s) and dysfunction; and (ii) the direct objects of in vitro expression and units of functional characterization and therefore in vitro test, systems for drug action.